Clinical intervention over the past two decades has changed HIV infection from a death sentence to a chronic disease. Despite pharmacological management of HIV-infection, approximately 50% of patients continue to present with neurologic impairment termed HIV-associated neurocognitive disorders (HAND), with persistent neuroinflammation and oxidative tissue damage. Current approaches to mitigate HAND have focused on agents targeting a single cellular function, which may limit their efficacy in a complex multisystem disease. Therefore, novel, pluripotent agents capable of acting simultaneously on diverse pathways and cellular processes may present an opportunity in the short and long term management of HIV. Thus, brain penetrant agents capable of controlling oxidative and inflammatory processes with minimal toxicity over prolonged administration to humans are attractive candidates in mitigating or preventing such effects associated with HAND. Our group has been investigating protective properties of secoisolariciresinol diglucoside (SDG), the main bioactive lignan phenolic in wholegrain flaxseed. Dietary SDG boosts endogenous antioxidant defenses in murine tissues, and exhibits potent anti-inflammatory and antioxidant activity in several tissues including the CNS. SDG and its metabolites can cross the blood-brain barrier (BBB) and enter brain tissues, making it an attractive candidate for mitigation of HIV-induced neurotoxicity. We therefore hypothesize that SDG, as a pluripotent agent, will mitigate HIV-associated neurotoxicity by reducing BBB damage, neuroinflammation, and oxidative stress. SDG is safe and well tolerated in humans and findings from numerous recent clinical trials enhance the translational aspect of our proposed study, which aims to provide novel insights into the usefulness of SDG, and to elucidate its mechanisms of action. Using in vitro modeling, Aims 1-3 will determine the effects of SDG on BBB damage, leukocyte trafficking across the BBB, microglial activation and neurotoxicity induced by HIV infection, and will elucidate mechanisms that underlie the efficacy of SDG as an agent that reduces neuroinflammation and oxidative stress. Aim 4 will investigate the ability of SDG to mitigate BBB damage, neuroinflammation, oxidative stress and neurotoxicity in the humanized mouse model of HIV infection, the huNSG-HIV mouse. Together, these studies will provide evidence to support SDG as adjunctive treatment for management of HAND.